Structure-activity relationship around PI-2620 highlights the importance of the nitrogen atom position in the tricyclic core.

Tau aggregates represent a critical pathology in Alzheimer's disease (AD) and other forms of dementia. The extent of Tau neurofibrillary tangles across defined brain regions corresponds well to the observed level of cognitive decline in AD. Compound 1 (PI-2620) was recently identified as a promising Tau positron emission tomography tracer for AD and non-AD tauopathies.

Lead Optimization Highlights the Importance of Off-Target Assays to Develop a PET Tracer for the Detection of Pathological Aggregated Tau in Alzheimer's Disease and Other Tauopathies.

The first candidate was tested in healthy controls and subjects with Alzheimer's disease (AD). As displayed off-target binding to monoamine oxidase A (MAO-A), a new lead with improved binding to Tau and decreased MAO-A binding was required. For compound optimization, Tau binding assays based on both human AD brain homogenate and Tau-paired helical filaments were employed.

Discovery of 2-(4-(2-fluoroethoxy)piperidin-1-yl)-9-methyl-9H-pyrrolo[2,3-b:4,5-c']dipyridine ([18F]PI-2014) as PET tracer for the detection of pathological aggregated tau in Alzheimer's disease and other tauopathies.

The compound screening was initiated with a direct staining assay to identify compounds binding to Tau aggregates and not Abeta plaques using human brain sections derived from late stage Alzheimer's disease donors. The binding of Tau aggregate selective compounds was then quantitatively assessed with human brain derived paired helical filaments utilizing the label-free Back Scattering Interferometry assay. In vivo biodistribution experiments of selected fluorine-18 labeled compounds were performed in mice to assess brain uptake, brain washout, and defluorination.

Discovery and preclinical characterization of [F]PI-2620, a next-generation tau PET tracer for the assessment of tau pathology in Alzheimer's disease and other tauopathies.

Purpose: Tau deposition is a key pathological feature of Alzheimer's disease (AD) and other neurodegenerative disorders. The spreading of tau neurofibrillary tangles across defined brain regions corresponds to the observed level of cognitive decline in AD. Positron-emission tomography (PET) has proved to be an important tool for the detection of amyloid-beta (Aβ) aggregates in the brain, and is currently being explored for detection of pathological misfolded tau in AD and other non-AD tauopathies.

THYROID PHANTOM MEASUREMENTS IN JOINT EURADOS-LLNL INTERCOMPARISON EXERCISE.

The European Radiation Dosimetry Group (EURADOS), in collaboration with Lawrence Livermore National Laboratory's (LLNL's) Thyroid Intercomparison Program (TRIP), conducted an intercomparison exercise consistent with the goals of EURADOS. In total, 35 in vivo radiobioassay facilities from 18 countries participated to evaluate the differences between the neck and thyroid phantoms specified in two standards issued by the American National Standards Institute. Radioiodine (125I and 131I) measurement results were compared to the traceable standard activity levels added to each phantom.

Discovery and characterization of novel indole and 7-azaindole derivatives as inhibitors of β-amyloid-42 aggregation for the treatment of Alzheimer's disease.

The aggregation of amyloid-β peptides into cytotoxic oligomeric and fibrillary aggregates is believed to be one of the major pathological events in Alzheimer disease. Here we report the design and synthesis of a novel series of indole and 7-azaindole derivatives containing, nitrile, piperidine and N-methyl-piperidine substituents at the 3-position to prevent the pathological self-assembly of amyloid-β. We have further demonstrated that substitution of the azaindole and indole derivatives at the 3 positions is required to obtain compounds with improved physicochemical properties to allow brain penetration.

Novel Phospho-Tau Monoclonal Antibody Generated Using a Liposomal Vaccine, with Enhanced Recognition of a Conformational Tauopathy Epitope.

The microtubule-associated protein Tau is an intrinsically unfolded, very soluble neuronal protein. Under still unknown circumstances, Tau protein forms soluble oligomers and insoluble aggregates that are closely linked to the cause and progression of various brain pathologies, including Alzheimer's disease. Previously we reported the development of liposome-based vaccines and their efficacy and safety in preclinical mouse models for tauopathy.

An Anti-β-Amyloid Vaccine for Treating Cognitive Deficits in a Mouse Model of Down Syndrome.

In Down syndrome (DS) or trisomy of chromosome 21, the β-amyloid (Aβ) peptide product of the amyloid precursor protein (APP) is present in excess. Evidence points to increased APP gene dose and Aβ as playing a critical role in cognitive difficulties experienced by people with DS. Particularly, Aβ is linked to the late-life emergence of dementia as associated with neuropathological markers of Alzheimer's disease (AD).

Historical review of lung counting efficiencies for low energy photon emitters.

This publication reviews the measured efficiency and variability over time of a high purity planar germanium in vivo lung count system for multiple photon energies using increasingly thick overlays with the Lawrence Livermore Torso Phantom. The measured variations in efficiency are compared with the current requirement for in vivo bioassay performance as defined by the American National Standards Institute Standard in ANSI Standard N13.30.

Engineering amyloid-like assemblies from unstructured peptides via site-specific lipid conjugation.

Aggregation of amyloid beta (Aβ) into oligomers and fibrils is believed to play an important role in the development of Alzheimer's disease (AD). To gain further insight into the principles of aggregation, we have investigated the induction of β-sheet secondary conformation from disordered native peptide sequences through lipidation, in 1-2% hexafluoroisopropanol (HFIP) in phosphate buffered saline (PBS). Several parameters, such as type and number of lipid chains, peptide sequence, peptide length and net charge, were explored keeping the ratio peptide/HFIP constant.

Efficacy and safety of a liposome-based vaccine against protein Tau, assessed in tau.P301L mice that model tauopathy.

Progressive aggregation of protein Tau into oligomers and fibrils correlates with cognitive decline and synaptic dysfunction, leading to neurodegeneration in vulnerable brain regions in Alzheimer's disease. The unmet need of effective therapy for Alzheimer's disease, combined with problematic pharmacological approaches, led the field to explore immunotherapy, first against amyloid peptides and recently against protein Tau. Here we adapted the liposome-based amyloid vaccine that proved safe and efficacious, and incorporated a synthetic phosphorylated peptide to mimic the important phospho-epitope of protein Tau at residues pS396/pS404.

TLR4- and TRIF-dependent stimulation of B lymphocytes by peptide liposomes enables T cell-independent isotype switch in mice.

Immunoglobulin class switching from IgM to IgG in response to peptides is generally T cell-dependent and vaccination in T cell-deficient individuals is inefficient. We show that a vaccine consisting of a dense array of peptides on liposomes induced peptide-specific IgG responses totally independent of T-cell help. Independency was confirmed in mice lacking T cells and in mice deficient for MHC class II, CD40L, and CD28.

Sequence-independent control of peptide conformation in liposomal vaccines for targeting protein misfolding diseases.

Synthetic peptide immunogens that mimic the conformation of a target epitope of pathological relevance offer the possibility to precisely control the immune response specificity. Here, we performed conformational analyses using a panel of peptides in order to investigate the key parameters controlling their conformation upon integration into liposomal bilayers. These revealed that the peptide lipidation pattern, the lipid anchor chain length, and the liposome surface charge all significantly alter peptide conformation.

A calibration phantom for direct, in vivo measurement of 241Am in the axillary lymph nodes.

A calibration phantom was developed at the University of Cincinnati (UC) to determine detection efficiency and estimate the quantity of activity deposited in the axillary lymph nodes of a worker who had unknowingly sustained a wound contaminated with 241Am at some distant time in the past. This paper describes how the Livermore Torso Phantom was modified for calibrating direct, in vivo measurements of 241Am deposited in the axillary lymph nodes. Modifications involved milling a pair of parallel, flat bottom, cylindrical holes into the left and right shoulders (below the humeral head) of the Livermore Torso Phantom in which solid, 1.

Mapping mandibular rest in humans utilizing electromyographic patterns from masticatory muscles.

As the mandible assumes its resting position in space, antagonistic muscles should assume their resting lengths as is demonstrated by resting and isometric electromyography. This zone of mandibular rest can be mapped using these physiologic parameters of muscle activity. Three positions were evaluated: a maximum physiologic open position, a maximum physiologic closed position, and a physiologic rest position.

Liposomal vaccines with conformation-specific amyloid peptide antigens define immune response and efficacy in APP transgenic mice.

We investigated the therapeutic effects of two different versions of Abeta(1-15 (16)) liposome-based vaccines. Inoculation of APP-V717IxPS-1 (APPxPS-1) double-transgenic mice with tetra-palmitoylated amyloid 1-15 peptide (palmAbeta(1-15)), or with amyloid 1-16 peptide (PEG-Abeta(1-16)) linked to a polyethyleneglycol spacer at each end, and embedded within a liposome membrane, elicited fast immune responses with identical binding epitopes. PalmAbeta(1-15) liposomal vaccine elicited an immune response that restored the memory defect of the mice, whereas that of PEG-Abeta(1-16) had no such effect.

Immunization with liposome-anchored pegylated peptides modulates doxorubicin sensitivity in P-glycoprotein-expressing P388 cells.

The clinical use of chemotherapy in cancer treatment is limited by the occurrence of multidrug resistance (MDR) associated with the overexpression of membrane transporters, one of the best known is P-glycoprotein (Pgp), that actively expels drugs out of tumor cells. To overcome Pgp-mediated MDR, synthetic peptides corresponding to fragments from extracellular loops 1, 2 and 4 of the murine Pgp were coupled to polyethylene glycol-distearoylphosphatidylethanolamine and inserted into empty or monophosphoryl lipid A-containing liposomes. This formulation elicited specific antibodies which blocked Pgp-mediated efflux of doxorubicin, resulting in increased intracellular drug accumulation and subsequent potentiation of the cytotoxic effect of doxorubicin on multidrug-resistant P388 (P388R) cells.

Telehealth screen for depression in a chronic illness care management program.

Chronic illness accounts for the majority of healthcare expenditures in the United States. Innovative telemedicine programs have been developed to help lessen the chronic illness burden, yet few have been developed to address comorbidity. Programs accommodating comorbidity are needed because most older adults suffer from two or more chronic illnesses.

DyNAs: constitutional dynamic nucleic acid analogues.

Dynamic cationic polymers were generated in aqueous media from functionally complementary monomers bearing nucleobase groups. (1)H NMR spectroscopy was used to follow the polycondensation reaction of the nucleobase-appended dihydrazides 1 and 2 with the dialdehydes B and C. The reversibility of these polymers was established by proton NMR spectroscopy through exchange of the dihydrazide 2 with polymer 1 B.

Techniques for reducing anesthetic injection pain: an interdisciplinary survey of knowledge and application.

Background: The authors conducted a study that considered family physicians' and dentists' knowledge and application of techniques to reduce the pain associated with anesthetic injections. They also assessed practitioners' discomfort with patients' injection pain and needle anxiety/phobia.

Methods: The authors designed a questionnaire about awareness and use of 10 techniques for reducing pain of anesthetic injection and mailed it to 2,000 randomly selected family physicians and general dentists.

Nucleic acid binding properties of thyminyl and adeninyl pyrrolidine-amide oligonucleotide mimics (POM).

Adeninyl POM was prepared using solid-phase peptide chemistry and shown to exhibit higher affinity for complementary DNA and RNA than the corresponding adeninyl PNA.

Financial risk relationships and adoption of management strategies in physician groups for self-administered injectable drugs.

Objective: To consider the extent, nature, and range of risk arrangements between physician groups and health maintenance organizations (HMOs) for self-administered injectable (SAI) drugs; to examine types and frequencies of SAI drug-use management strategies adopted by physician groups; and to explore the relationship between locus and level of financial risk for SAIs and physician group strategy adoption.

Methods: We used a multiple case-study design to select physician groups and their health maintenance organization (HMO) contractual partners in 4 markets in the United States (Northwest, Northeast, Midwest, Southwest). Physician groups in these markets were chosen based on size (e50 physicians) and experience with drug risk (e1 year).